CN107666913B - Tesofensine, beta-receptor blocker combination formulations - Google Patents

Abstract

The present invention relates to a controlled release formulation comprising the active compound tesofensine and a beta-blocker such as metoprolol or carvedilol or a pharmaceutically acceptable salt thereof. The invention further relates to the use of the controlled release formulation in a method of treating diabetes, obesity or obesity related diseases.

Description

Tesofensine, beta-receptor blocker combination formulations

Technical Field

The present invention relates to a novel controlled release formulation comprising the active compound tesofensine (tesofensine) and a beta blocker (beta blocker) such as metoprolol (metoprolol) or carvedilol (carvedilol) or a pharmaceutically acceptable salt thereof.

Background

Over the past few decades, obesity has increased in prevalence in almost all ethnic, and socioeconomic populations, regardless of gender and age. Obesity causes a significant increase in the risk of: type 2 diabetes, coronary heart disease, hypertension and numerous other major diseases and overall mortality from all causes. Therefore, for obese patients, weight loss is crucial. Thus promoting the creation of new and alternative treatments for managing obesity.

Tesofensine, [ (1R,2R,3S,5S) -3- (3, 4-dichlorophenyl) -2- (ethoxymethyl) -8-methyl-8-azabicyclo [3.2.1] octane ], first described in WO 97/30997, is a triple monoamine reuptake inhibitor in the development of obesity treatment regimens.

Tesofensine is effective in inducing weight loss in obese individuals, about twice as much as is seen with currently available weight loss drugs. The results of clinical studies with tesofensine also show that this compound has good safety and good tolerability. However, although no clinically relevant cardiovascular adverse events or changes were seen in blood pressure or pulse, some cardiovascular effects were measured, with a slight increase in heart rate and a tendency for blood pressure to increase. While such small effects do not pose a direct risk to the patient, some medical and regulatory concerns have been raised based on the following observation studies: even small changes in cardiovascular parameters may have long-term consequences for the benefit/risk assessment of the patient.

Preclinical and clinical data indicate that appetite suppression is an important mechanism by which tesofensine exerts its potent weight loss effects. In particular, a strong binge response to tesofensine treatment (i.e. reduced appetite, reduced eating) was demonstrated to be associated with central stimulation of noradrenergic neurotransmission and dopaminergic neurotransmission. However, it has been observed in clinical settings that the sympathomimetic pattern of tesofensine may also lead to increased heart rate and blood pressure.

Beta-blockers, (beta-blockers, beta-adrenoceptor blockers, beta antagonists, beta-adrenoceptor antagonists, or beta-adrenoceptor antagonists) are a class of drugs commonly used to treat cardiac arrhythmias, protect the heart from a second heart attack (myocardial infarction) after the first heart attack (secondary prevention), and in some cases, protect against hypertension. The heart rate reducing effect of beta-blockers is also well known.

Metoprolol, 1- (isopropylamino) -3- [4- (2-methoxyethyl) -phenoxy ] -propan-2-ol, known by various trade names, is a selective beta 1 (epinephrine) receptor blocker, commonly used in the treatment of various diseases of the cardiovascular system, in particular hypertension.

Carvedilol ((±) - [3- (9H-carbazol-4-yloxy) -2-hydroxypropyl ] [2- (2-methoxyphenoxy) ethyl ] amine) is a mixed, i.e., non-selective, α and β -blocker. It is sold under various trade names and is traditionally used to treat mild to severe Congestive Heart Failure (CHF) and hypertension.

WO 2013/120935 describes the treatment of obesity by co-administration of tesofensine and metoprolol in order to ameliorate drug-induced blood pressure rise or heart rate increase.

The serum half-life of tesofensine is 9 days (Bara-Jimenez W, Dimitrova T, Sherzani A, Favit A, Mouradian MM, Chase TN (2004). "Effect of monoamine reuptake inhibitor NS 2330in advanced Parkinson's disease". Mov Disord 19 (10): 1183-6.). In contrast, the half-life of beta blockers is quite short, with metoprolol having a half-life of about 3-4 hours and carvedilol having a half-life of about 7 to 10 hours. Thus, simultaneous daily administration of these two drugs may induce high fluctuations in blood levels of the beta-blocker and potentially reproduce the therapeutic efficacy of the temporary absence of the beta-blocker.

Disclosure of Invention

The present patent application relates to pharmaceutical compositions comprising

a. A first composition comprising an extended release composition of an Active Pharmaceutical Ingredient (API) selected from a beta blocker or a pharmaceutically acceptable salt thereof,

b. a second composition comprising an Active Pharmaceutical Ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof, and

c. a third composition comprising an immediate release composition of an Active Pharmaceutical Ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof.

The pharmaceutical composition is effective in treating obesity without causing undesirable increases in heart rate and blood pressure as observed with tesofensine alone. The release profiles of the three components of the pharmaceutical composition are carefully selected to prevent side effects while maintaining the therapeutic efficacy of tesofensine.

The beta-blocker may, for example, be selected from metoprolol, carvedilol or a pharmaceutically acceptable salt thereof.

The second composition may be a first coating applied to the first composition.

The third composition may be a second coating applied to the first coating.

The first composition may be coated with a coating comprising the second composition and the third composition.

The first composition may constitute a core coated with a coating comprising the second composition and the third composition. Alternatively, the first composition may comprise a core coated with a first coating comprising the second composition, wherein the first layer is coated with a second coating comprising the second composition.

In some embodiments, the first composition comprises a pill comprising:

a. an inert pellet core;

b. a drug layer comprising the active pharmaceutical ingredient, the layer overlying the inert core; and

c. a controlled release layer thereon.

The inert core comprises a sugar pellet coated with a plasticized film-coated subcoating of a hydrophobic film-coating polymer plasticized with a hydrophilic plasticizer and a hydrophobic plasticizer; the drug layer comprises an API and a binder; the controlled release layer comprises a plasticized film coating of a hydrophobic film coating polymer plasticized with a hydrophilic plasticizer and a hydrophobic plasticizer, and wherein the pill is mixed with a final tableting blend (e.g., a final tableting blend comprising a powder mixture of one or more of fillers, disintegrants, glidants and/or lubricants).

In one embodiment, the hydrophobic film coating polymer comprises ethyl cellulose, the hydrophilic plasticizer comprises polyethylene glycol, the hydrophobic plasticizer comprises dibutyl sebacate, the API is metoprolol succinate, the binder comprises povidone, and the powder mixture comprises STARLAC (an excipient that is 85% alpha-lactose monohydrate and 15% white corn starch) (MEGGLE Group, Germany), SYLOID (silicon dioxide) (w.r.grace & Co.), crospovidone, and magnesium stearate.

In another embodiment, the extended release layer comprises a mixture of:

a. an ethyl acrylate/methyl methacrylate copolymer,

b. a surfactant, and

c. the sodium stearyl fumarate is added with sodium stearyl fumarate,

wherein the controlled release layer has been deposited from an aqueous liquid and the ethyl acrylate/methyl methacrylate copolymer is present in the film coating in an amount in the range of 80-99.5% (w/w).

The composition may be in the form of a pharmaceutical dosage form, such as a tablet or capsule. The tablets may contain an outer cosmetic film coat.

In another aspect, the composition is used in a method of treating, preventing or ameliorating obesity or an obesity-related disorder.

In yet another aspect, the present invention relates to the use of a composition as described herein for the manufacture of a medicament for the treatment of obesity or obesity related diseases.

The obesity-related disease may be a disease or condition selected from: type 2 diabetes, pre-diabetes, type 1 diabetes (diabetes), metabolic syndrome, dyslipidemia, atherosclerosis, drug obesity, binge eating disorder, bulimia nervosa, binge eating disorder, compulsive binge eating, impaired appetite regulation, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

In one embodiment, the obesity-related disease or condition is type 2 diabetes.

In one embodiment, the obesity-related disease or condition is non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis (NASH).

In another aspect, the composition is for use in a method of treating, preventing or ameliorating diabetes, preferably type 2 diabetes.

In another aspect, the compositions are used in a method of treating, preventing or ameliorating nonalcoholic fatty liver disease (NAFLD) and/or nonalcoholic steatohepatitis (NASH).

In another aspect, the composition is used in a method of reducing liver fat and/or visceral obesity.

Preferably, the composition is administered once daily.

Drawings

FIG. 1: the calculated dissolution profile of metoprolol over 24 hours using a USP type II apparatus, rotating paddles, with 900ml phosphate buffer at pH 7.4, 37 ℃ at a set rotation speed of 75 rpm.

FIG. 1A: calculated dissolution profiles for tablets containing 25mg immediate release metoprolol and 100mg delayed release metoprolol.

FIG. 1B: calculated dissolution profiles for tablets containing 10mg immediate release metoprolol and 100mg delayed release metoprolol.

FIG. 2: schematic section of a tablet with a delayed release phase (A) of beta-blocker, an immediate release phase (B) of beta-blocker and a tesofensine phase (C).

FIG. 2A: a three-layered tablet having one delayed release core of beta-blocker and two immediate release beta-blocker and tesofensine coatings.

FIG. 2B: as with 2A, except that the order of coating is reversed.

FIG. 2C: two-layer tablets having a core of extended release of the beta-blocker and a coating of immediate release of the beta-blocker and tesofensine.

FIG. 2D: a one-layer tablet having delayed release spheres/granules of beta-blocker in an adhesive matrix comprising immediate release of beta-blocker and tesofensine.

FIG. 3: release of metoprolol from the following tablets: metoprolol 100mg extended release tablet with tesofensine/metoprolol film applied in combination (example 7); and metoprolol 100mg extended release tablets with tesofensine film, and metoprolol immediate release film administered separately (example 6).

FIG. 4: expected dissolution profile of carvedilol in a pharmaceutical product comprising 80mg of delayed release carvedilol and 20mg of immediate release carvedilol.

Definition of

delayed-ER-also known as sustained release [ SR ], delayed release [ ER, XR, XL ], and controlled release [ CR ], are mechanisms used in tablets or capsules to allow dissolution of the drug over time for slower and more stable release into the bloodstream.

Immediate release-IR. The drug is released (dissolved) immediately after ingestion.

Detailed Description

The present application discloses a pharmaceutical composition comprising two different phases of a beta-blocker, and one phase of tesofensine. One phase of the beta-blocker is an extended release phase and the other phase of the beta-blocker is an immediate release phase.

The beta-blocker may be, for example, metoprolol or carvedilol or a pharmaceutically acceptable salt thereof. These include phosphates, succinates, maleates, sulfates, glutarates, lactates, benzoates, and mandelates.

The in vitro biosolution curve of the beta blocker (measured by USP type II apparatus, rotating paddles, with 500ml phosphate buffer at pH 7.4, 37 ℃ at a set rotation speed of 75 rpm) is preferably as follows:

time of dissolution	Dissolution range
		1 hour	10-35％
4 hours	25-45％
		8 hours	45-65％
20 hours	>80％

For example, the in vitro biosolution profile of a combination of metoprolol preferably has a dissolution profile within the following ranges: ER ratio for different metoprolol one or more of the following release ranges (measured by USP type II apparatus, rotating paddles, with 900ml phosphate buffer at pH 7.4, set rotation speed of 75rpm at 37 ℃) at each time point.

Typically, the tesofensine of the composition dissolves within 1/2-1 hour. The in vitro dissolution profile using tesofensine under the above conditions was such that at least 80% of the API was dissolved within 45 minutes.

Many physiological factors affect both the transit time of the gastrointestinal tract and the release of drug from a controlled release dosage form, and thus the uptake of drug into the systemic circulation. The sustained release dosage form should release the beta blocker at a controlled rate such that the amount of active ingredient available to the body to treat the condition remains at a relatively constant level for an extended period of time. The release of the active ingredient from a controlled release dosage form is typically controlled by diffusion through the coating.

It is also important that the portion of the beta blocker is released rapidly so that a therapeutically effective level of the beta blocker is quickly achieved.

Tesofensine

The pharmaceutical compositions described herein comprise an Active Pharmaceutical Ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof.

Tesofensine [ (1R,2R,3S,5S) -3- (3, 4-dichlorophenyl) -2- (ethoxymethyl) -8-methyl-8-azabicyclo [3.2.1] octane ] is a central nervous system-acting triple Monoamine Reuptake Inhibitor (MRI) with intrinsic inhibitory activity on norepinephrine, serotonin and dopamine transport functions. When corrected for placebo and dietary effects, long-term tesofensine treatment resulted in approximately 10% weight loss in obese patients, which was as much as twice the effect achieved by the current commercial antiobesity drugs.

The chemical structure of tesofensine is

Preclinical and clinical data indicate that appetite suppression is an important mechanism by which tesofensine exerts its potent weight loss effects. Moreover, tesofensine has also been shown to increase nocturnal activity energy expenditure in human subjects. These findings have been recently confirmed and expanded in the preclinical setting, suggesting that tesofensine induces a strong and long lasting weight loss in a rat model of Diet Induced Obesity (DIO), which is caused by appetite suppression and a gradual increase in energy expenditure. In particular, the binge effect of tesofensine in DIO rats is critically dependent on stimulated α 1 adrenergic receptor activity, as well as the less extended function of the dopamine D1 receptor, suggesting that enhancement of central stimulation by noradrenergic and dopaminergic neurotransmission constitutes an important mechanism for the potent appetite suppression effect of tesofensine.

Overall, chronic tesofensine treatment causes fewer adverse events and causes minimal cardiovascular effects, suggesting that tesofensine can generally treat obesity well-tolerated for long periods. However, a dose-dependent increase in heart rate and a significant increase in blood pressure have been reported in obese individuals. The long-term consequences of this tesofensine-induced cardiovascular effect are not known and may potentially affect the benefit/risk assessment of patients treated with tesofensine.

BETA-receptor blocking agent

The present invention relates to the use of beta-blockers. The beta-blocker can be any conventional beta-blocker known in the art. Preferably, the beta-blocker is selected from the group of compounds known in the art and commercially available under different trade names or obtainable as described in the literature.

Non-selective beta-receptor blockers

In one embodiment, the beta-blocker is a non-selective beta-blocker. Examples of non-selective beta-blockers include allylalol, sulfamolol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

In one embodiment, the beta-blocker is selected from the group consisting of allylol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and pharmaceutically acceptable salts thereof.

BETA-RETARDER FOR BETA 1 RECEPTOR SELECTION

In another embodiment, the beta-blocker is a beta 1 receptor selective beta-blocker.

Examples of β 1 receptor selective β -blockers include acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol, and nebivolol.

In one embodiment, the beta-blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol, nebivolol and pharmaceutically acceptable salts thereof.

In a particular embodiment, the beta blocker is metoprolol or a pharmaceutically acceptable salt thereof.

Mixed alpha and beta-receptor blockers

In still other embodiments, the beta-blocker is a mixed alpha and beta-blocker.

Examples of mixed alpha and beta-blockers include carvedilol, celiprolol, and labetalol.

In one embodiment, the beta-blocker is selected from carvedilol, celiprolol, labetalol, and pharmaceutically acceptable salts thereof.

In a particular embodiment, the beta blocker is carvedilol or a pharmaceutically acceptable salt thereof.

BETA-RETARDER SELECTIVE BETA-RETARDER

In still other embodiments, the beta-blocker is a beta 2 receptor selective beta-blocker.

An example of a β 2 receptor selective β -receptor blocker is butaxamine.

In one embodiment, the beta-blocker is butaxamine or a pharmaceutically acceptable salt thereof.

Pharmaceutically acceptable salts

Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, pamoate, heptanoate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, tosylate, and the like. These salts may be formed by procedures well known and described in the art.

Examples of pharmaceutically acceptable cationic salts of APIs include, but are not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine salts of APIs containing cationic groups

Salts (lysine), and ammonium salts, and the like. Such cationic salts can be formed by procedures well known and described in the art.

In the context of this application, of N-containing compounds "

Salts "are also useful as pharmaceutically acceptable salts. Preferably "

Salts "include alkyl-

Salt, cycloalkyl-

Salts, and cycloalkylalkyl-

And (3) salt.

In one embodiment of the present application, tesofensine is selected from the group consisting of the free base, citrate and tartrate.

Suitable pharmaceutically acceptable salts of metoprolol include any of the salts mentioned herein, and preferably include tartrate, succinate, fumarate or benzoate salts, especially succinate salts. The S-enantiomer of metoprolol or a salt thereof, particularly a benzoate or sorbate salt, may also be used.

Similarity factor

The similarity factor (f2) is a recognized method for determining the similarity between the dissolution profiles of a reference and a test compound. The similarity factor (f2) is a logarithmic transformation of the sum of squared errors. When the test curve and the reference curve are the same, the similarity factor (f2) is 100, and the similarity factor (f2) gradually approaches 0 as the difference increases. Similarity factors have also been adapted for use in determining the similarity between the dissolution profiles of the reference and test compounds as they relate to sustained and controlled release formulations such as those exemplified herein.

f2 similarity factors were adopted in the SUP AC guidelines and were FDA directed to Dissolution Testing for Immediate Release Dosage Forms (FDA industry guidelines, Dissolution Testing for Immediate Release Solid Oral Dosage Forms (Dissolution Testing of Immediate Release Solid Oral Dosage Forms), FDA, (CDER), August 1997(Dissolution Tech.4, 15-22, 1997)).

Preferably, the pharmaceutical composition has an in vitro dissolution profile of the beta blocker using a USP type II apparatus, rotating paddle method as described herein, with a similarity factor (f2) of from 50 to 100, when calculated using one of the examples from figure 1 or figure 3 as a reference profile.

Amount and ratio of API

The ratio of delayed release beta-blocker (e.g. metoprolol) to immediate release beta-blocker can be 75-95: 25-5. Suitably, the beta blocker, e.g., metoprolol, is present in the dosage form in a ratio of extended release to immediate release of about 80: 20. In another embodiment, a beta blocker, such as metoprolol, is present in a ratio of extended release to immediate release of about 90:10 or 100: 10. In yet another embodiment, the ratio is about 80:20 or 75: 25. Explained another way, for a unit dosage form, such as a tablet containing 125mg of a beta-blocker (e.g., metoprolol), the beta-blocker is present in an amount of about 100mg in the delayed release phase and about 25mg in the immediate release phase. For a unit dosage form containing 110mg of a beta-blocker, such as metoprolol, the delayed release beta-blocker can be present in an amount of 100mg and the immediate release beta-blocker can be present in an amount of 10 mg. For example, in one embodiment, the ratio of the extended release phase to the immediate release phase represents a proportional amount of each layer in a bilayer dosage form. In another embodiment, the ratio represents the amount of metoprolol in the delayed release intragranular component of a monolayer dosage form compared to the amount of metoprolol in the immediate release extragranular component of a monolayer dosage form. The ratios and amounts mentioned in this paragraph also apply to metoprolol as a beta-receptor blocker.

Preferably, a dosage form comprises an amount of a delayed release beta blocker, such as metoprolol, such that it provides 25-200mg of API, such as 50-200mg of API, preferably 50-150mg of API, such as 75-125mg of API, such as about 80mg or about 100mg of API.

Other beta blockers may require lower doses. In this case, a dosage form may comprise an amount of a delayed release beta-blocker, such as carvedilol, such that it provides 10-100mg of API, such as 20-100mg of API, preferably 30-80mg of API, such as about 20mg of API, 40mg or about 80mg of API.

The amount of tesofensine (in the second composition) is typically 0.1-1mg of API, preferably 0.2-0.8mg of API, such as 0.25-0.75mg of API, such as 0.4-0.6mg of API, such as about 0.25mg of API, 0.5mg or 0.75mg of API, for each dose.

The amount of immediate release beta blocker, e.g., metoprolol, may be 5-100mg of API, e.g., 50-80mg of API, preferably 10-75mg of API, e.g., 10-50mg of API, e.g., 20-30mg or 10-20mg of API, e.g., about 5mg of API, about 10mg of API, about 15mg of API, or about 25mg of API, for each dose.

Thus a dosage form may comprise: 50-200mg of a delayed release beta-blocker, such as metoprolol, 5-50mg of an immediate release beta-blocker, such as metoprolol, and 0.1-1.5mg of tesofensine; e.g., 75-125mg of a delayed release beta-blocker, e.g., metoprolol, 10-25mg of an immediate release beta-blocker, e.g., metoprolol, and 0.25-0.75mg of tesofensine; e.g., 75-80mg of a delayed-release beta-blocker, e.g., metoprolol, 10-15mg of an immediate release beta-blocker, e.g., metoprolol, and 0.25-0.75mg of tesofensine; e.g., 75-85mg of a delayed-release beta-blocker, e.g., metoprolol, 15-25mg of an immediate release beta-blocker, e.g., metoprolol, and 0.25-0.75mg of tesofensine; for example, 90-110mg of a delayed release beta-blocker, such as metoprolol, 20-30mg of an immediate release beta-blocker, such as metoprolol, and 0.25-0.75mg of tesofensine.

Thus a dosage form may comprise: 20-100mg of an extended release beta-blocker, such as carvedilol, 5-40mg of an immediate release beta-blocker, such as carvedilol, and 0.1-1.5mg of tesofensine; e.g., 30-80mg of an extended release beta-blocker, e.g., carvedilol, 5-20mg of an immediate release beta-blocker, e.g., carvedilol, and 0.25-0.75mg of tesofensine; for example, 40-80mg of a delayed release beta-blocker, such as carvedilol, 10-20mg of an immediate release beta-blocker, such as carvedilol, and 0.25-0.75 tesofensine.

In one embodiment, the beta-blocker is metoprolol and the amounts of the two APIs in the three phases of the dosage form are expressed as absolute amounts as follows.

Extended release of metoprolol	Metoprolol quick release	Tesofensin quick release
			50-200mg	5-50mg	0.1-1.5mg
75-125mg	10-25mg	0.25-0.75mg
			75-80mg	10-15mg	0.25-0.75mg
100mg	25mg	0.5mg
			100mg	10mg	0.5mg
80mg	20mg	0.5mg

In one embodiment, the beta-blocker is carvedilol and the amounts of the two APIs in the three phases of the dosage form are expressed as absolute amounts as follows.

Extended release of carvedilol	Immediate release of carvedilol	Tesofensin quick release
			20-100mg	5-25mg	0.1-1.5mg
30-80mg	5-20mg	0.25-0.75mg
			80mg	20mg	0.25-0.75mg
40mg	10mg	0.5mg
			20mg	5mg	0.5mg

Multilayer dosage form

The extended release phase may be part of a multilayer tablet, such as a bilayer or trilayer dosage form.

In one embodiment, the dosage form comprises three layers of dosage units having: an Extended Release (ER) phase layer containing a beta-blocker such as metoprolol or carvedilol, and an immediate release phase layer containing a beta-blocker such as metoprolol or carvedilol, and another immediate release layer containing tesofensine. The extended release phase comprises a therapeutically effective amount of a beta-blocker, such as metoprolol or carvedilol, suitably in the form of particles.

In other embodiments, the dosage form is a bilayer tablet having one extended release phase layer containing a beta-blocker, such as metoprolol or carvedilol, and one immediate release layer containing both a beta-blocker (such as metoprolol or carvedilol) and tesofensine.

Delayed release phase

Extended release compositions of beta-blockers (e.g., metoprolol or pharmaceutically acceptable salts of metoprolol) are known in the art. Non-limiting examples of disclosures of such compositions can be found in: WO 2015/004617, WO 2013/084089, WO 2013/030725, WO 2012/052834, WO 2011/143420, WO 2007/09770, WO 2004/069234, WO 2007/110753, WO 2007/029070, WO 2008/012346, and WO 2007/048233. Such extended release compositions typically involve coating the API with a release-retarding layer that provides a near zero order API dissolution rate.

In one embodiment, the delayed release beta-blocker (e.g., metoprolol) is formulated as a pill with a pharmaceutical excipient such as, for example, a binder, a film coating polymer, a plasticizer, a starch, a glidant, and a disintegrant.

Extended release formulations of carvedilol are also described in US 8,101,209(flame Technologies).

Inert core

In some embodiments, the pellet comprises an initial core (inert core) coated with a layer of a beta-blocker, such as metoprolol or a metoprolol salt, and further coated with a release-retarding layer.

As used herein, the term primary core refers to a pharmaceutical core for a pharmaceutical formulation in which the core is inert.

In one embodiment, a pharmaceutical composition for extended release is provided comprising pills coated with a beta-blocker, such as metoprolol or a metoprolol salt, wherein each coated pill comprises a) an inert core comprising at least 50% (w/w) of a soluble substance; b) a drug layer comprising a beta-blocker such as metoprolol, the layer covering the inert core; and c) a controlled release layer thereon.

In another embodiment, a pharmaceutical composition is provided wherein the release of a drug from a pill portion of a pharmaceutical composition comprising a tabletted or encapsulated composition comprising a plurality of pills is controlled by the amount or percentage of the initial core/spheres of the pill. Preferably, the amount of the initial core is from about 15% to about 35% by weight, e.g., 20-30%, of the controlled release coated pill prior to tableting or capsule filling.

In another embodiment, the inert core is reinforced by applying a subcoating to the initial core/sphere. In a pharmaceutical composition in which pills containing a drug are compressed into tablets, the drug pills are mixed with a powder excipient to form a tableting blend. However, the size of the drug-coated pellets is typically larger than the particle size of the powder excipients, which can cause the tableting blend to be non-uniform. The preferred homogeneity of the compressed blend is such that the average test of compressed blend samples each having a weight equal to one tablet is in the range of 90% to 110% of the label dose and the relative standard deviation of the individual tests is less than or equal to 5%. Therefore, the size of the medication pill is preferably small. When a large amount of drug is clad on a small primary core, a high degree of stress is applied to the primary core. Such stresses can cause wear, particularly when the inert core contains sugar pellets. To provide a higher degree of mechanical strength of the inert core without altering the dissolution rate of the drug coated pellets, a subcoating may be applied over the initial core/sphere. Preferably, the amount of subcoating is from about 10% to about 40% based on the total weight of the subcoated inert core, more preferably, the amount of subcoating is from about 15% to about 30% based on the total weight of the subcoated inert core, and most preferably, the amount of subcoating is from about 16% to about 20% based on the total weight of the subcoated inert core.

The inert core of each pellet in the pharmaceutical composition may comprise from about 50% to about 100% (by weight) of the soluble material. Preferably, the inert core comprises from about 70% to about 90% (by weight) of soluble material. A preferred initial core comprises a sugar pellet. Dragees have been used as excipients in the pharmaceutical industry. Such dragees for pharmaceutical compositions typically contain not more than 92% sucrose, calculated on a dry weight basis, the remainder consisting of corn starch. Usually sugar pellets with a core size of more than 500 μm are used. The inert core, preferably sugar pellets, have a core size of from about 50 μm to about 500 μm, preferably from about 100 μm to about 400 μm, more preferably from about 250 μm to about 350 μm.

The inert core may comprise an initial core/sphere that is subcoated with a plasticized film coating polymer. This subcoating of the initial core/ball provides mechanical strength to the inert core. The film coating polymer may be a hydrophobic polymer or a hydrophilic polymer, or a combination of both. Suitable film coating polymers may be cellulose derived polymers or polymethacrylate polymers. Furthermore, a hydrophobic polymer or a hydrophilic plasticizer or a combination of several plasticizers may be used to plasticize the film coating polymer. These compounds are mixed with a solvent prior to applying the polymer-coated subcoating to the initial core/sphere. Suitable solvents for mixing the polymer-coated subcoating compound are selected from the group consisting of ethanol, isopropanol, acetone and purified water. For example, a mixture of ethanol, acetone and water is preferably used to mix the preferred subcoating compound ethylcellulose (as the film coating polymer), and the plasticizers dibutyl sebacate and polyethylene glycol (EC, DBS and PEG).

Preferably, the initial core/sphere is a sugar pellet coated with a mixture of sub-coatings of polymers such as cellulose derivatives such as ethyl cellulose and triethyl citrate, polyethylene glycol, dibutyl sebacate, and dibutyl phthalate, and wherein the sub-coating on the initial core/sphere does not alter the drug release rate of the pharmaceutical composition. A preferred subcoating on a dragee comprises: ethyl cellulose as a hydrophobic film coating polymer, and a combination of two or more plasticizers, at least one hydrophilic plasticizer and at least one hydrophobic plasticizer. Suitable plasticizers may include, for example, polyethylene glycol, citric acid esters, dibutyl sebacate, diethyl phthalate, and triacetin. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as hydrophilic plasticizer and hydrophobic plasticizer, respectively. Preferably, the subcoating comprises about 75% to about 85% by weight ethylcellulose, about 10% to about 20% by weight polyethylene glycol, and about 3% to about 7% by weight dibutyl sebacate, based on the weight of the subcoating. More preferably, the subcoating comprises 80% by weight of ethylcellulose, 15% by weight of polyethylene glycol and 5% by weight of dibutyl sebacate, based on the weight of the subcoating.

Alternatively, the core may be an insoluble core onto which the active ingredient has been deposited, for example by spraying. The core may be made of silica, glass or plastic resin particles. Suitable types of plastic materials are pharmaceutical plastics such as polypropylene or polyethylene, preferably polypropylene. Suitable insoluble cores may have a diameter of from 0.01 to 2mm, preferably from 0.05 to 1.0mm, more preferably from 0.1 to 0.7 mm.

BETA-acceptor blocking agent for delayed release

In one embodiment, a beta-blocker, such as metoprolol or a pharmaceutically acceptable salt thereof, can be applied to the inert core. No "class 2" solvent (defined by FDA) is required to administer the Active Pharmaceutical Ingredient (API) drug onto the inert core to form a drug-coated pill. FDA defines "class 2" solvents as having intrinsic toxicity. The active ingredient is dispersed in water, preferably with an acceptable binder excipient such as, but not limited to, polyvinylpyrrolidone, cellulose derivative polymers, or starch.

Beta-blockers such as metoprolol can be administered as a dispersion rather than a solution. It is therefore preferred that the drug substance has physical properties such that it will be possible to prepare drug-coated pellets in high yield. Accordingly, the drug substance preferably has a particle size distribution such that the d (0.9) value is less than about 80 μm. Preferably, the d (0.9) value of the particle size distribution of the drug substance is less than about 50 μm, more preferably less than about 30 μm. Thus, concentrated dispersions for application can be prepared, which can shorten the preparation time.

The drug-coated pill can comprise from about 40% to about 90% (by weight) of the drug layer, preferably from about 50% to about 80% (by weight), more preferably from about 55% to about 75% (by weight).

Other beta-blockers such as carvedilol or its salts can be administered in a similar manner as indicated for metoprolol.

Controlled release layer

The last layer applied on the alkyl group is the layer that controls the release of the active pharmaceutical ingredient. The size of the pellets that have been coated with the controlled release layer is from about 200 μm to about 800 μm. Preferably, the size of the pellets coated with the controlled release layer is about 300 μm to about 700 μm, more preferably about 400 μm to about 600 μm. Also, the controlled-release layer may contain water-soluble or insoluble components. Such components may be a film-forming polymer and a plasticizer. For example, a film comprising a polymer layer may be applied to a drug-coated pill.

Three different types of extended release coatings are described below.

A first extended release coating.

In one embodiment, the extended release film coating comprises i) an acrylic polymer, ii) a surfactant and iii) sodium stearyl fumarate, wherein said film coating has been deposited from an aqueous liquid.

Typically, the film coating composition comprises

a)25 to 35 weight percent acrylic polymer dispersion

b)0.1 to 4% by weight of a surfactant

c) From 0.1 to 4% of sodium stearyl fumarate, and

d) an aqueous liquid which brings the total amount to 100%.

In one embodiment, a film coating suitable for delivering delayed release is provided. Suitably, the acrylic polymer used in this case comprises homogeneous particles in which the T of the polymer or copolymer is in an aqueous dispersion_g<T of polymer or copolymer at room temperature, but in dry state_g>And (4) room temperature. Suitable polymers include: acrylic acid and its esters, in particular methyl, ethyl, propyl and butyl esters; and methacrylic acid and its esters, especially methyl, ethyl, propyl and butyl esters. A particularly preferred polymer is Eudragit, trade name

(Rohm Pharma) or Eudragit

(Rohm Pharma). Optionally, other detackifiers may be required.

Suitably, the amount of acrylic polymer in the film coating composition is from 15 to 50 wt%. Preferably, the amount of acrylic polymer in the film coating composition is 20 to 40 wt.%. More preferably, the amount of acrylic polymer in the film coating composition is from 25 to 35 wt%.

Suitably, the surfactant is one of: nonionic surfactants, such as sorbitan esters (Span series); polysorbates (Tween series); polyoxyethylated glycol monoethers (e.g., the Brij series); polyoxyethylated alkylphenols (such as the Triton series or the Igepal series); alkyl glycosides (e.g., dodecyl maltoside); sugar fatty acid esters (e.g., sucrose laurate); saponins; and the like, or mixtures thereof; amphoteric surfactants, such as betaine; anionic surfactants such as sulfated fatty alcohols, e.g., sodium dodecyl sulfate SDS; sulfated polyoxyethylated alcohols; other materials, such as dioctyl sulfosuccinate; bile salts (e.g., dihydroxybile salts such as sodium deoxycholate, trihydroxybile salts such as sodium glycocholate, etc.); fusidate salts (e.g. sodium dihydrofusidate); and the like; cationic surfactants such as ammonium compounds; soaps, fatty acids, and lipids and salts thereof, such as alkanoic acids; (e.g., caprylic acid, oleic acid); monoglycerides (e.g., glycerol monooleate), phospholipids, which are neutral or positively or negatively charged (e.g., dialkyl lecithins, dialkyl phosphatidylserines, etc.); and the like; more preferably, the surfactant is a nonionic surfactant. Most preferably, the surfactant is nonoxynol 100.

Suitably, the amount of surfactant in the film coating composition is from 0.05 to 8% by weight. Preferably, the amount of surfactant in the film coating composition is from 0.1 to 6% by weight. More preferably, the amount of surfactant in the film coating composition is from 0.5 to 4% by weight.

In a most preferred embodiment, the acrylic polymer and surfactant are prepared from

NE30D is provided in a composition, film coating or formulation as defined previously.

Suitably, the amount of sodium stearyl fumarate in the film coating composition is from 0.05 to 8% by weight. Preferably, the amount of sodium stearyl fumarate in said film coating composition is from 0.1 to 6% by weight. More preferably, the amount of sodium stearyl fumarate in said film coating composition is from 0.5 to 4% by weight.

Suitably, the aqueous liquid comprises water and an organic liquid which is miscible with water, for example a lower alkanol such as ethanol, propanol or isopropanol. From a safety point of view it is preferred that the proportion of organic liquid is kept to a minimum, but small amounts are tolerable, e.g. 0 to 20% by volume. Preferably, the liquid is water.

The film coating composition is particularly suitable for use as an aqueous film-coating composition, wherein the film-coating is applied using water as the liquid. When the liquid is water, the latex is preferably a poly (ethyl acrylate-co-methyl methacrylate) copolymer, such as Eudragit

(Rohm Pharma). TheThe process is particularly advantageous because it does not require the use of environmentally unacceptable organic solvents, some of which also present processing problems due to flammability, and also eliminates many of the problems experienced with aqueous coatings described above.

Second extended release coating

Alternatively, the film may comprise at least one film coating polymer and may be plasticized with one or more plasticizers. These plasticizers may vary in their degree of solubility (hydrophobicity/hydrophilicity). By varying the ratio between the plasticizer and the film coating polymer, or between different plasticizers (if more than one is used), the rate of release of the drug from the pellet formulation can be controlled. The controlled release layer for delayed release of the beta-blocker may comprise a hydrophobic film coating polymer, such as ethylcellulose, and a combination of at least two plasticizers, at least one hydrophilic plasticizer and one hydrophobic plasticizer, such as polyethylene glycol and dibutyl sebacate. Preferably, the ratio of the hydrophobic plasticizer to the hydrophilic plasticizer in the controlled release layer of the pharmaceutical composition is 3:1 to 1:3, more preferably, the ratio is 1: 1.

In addition, the controlled release layer may comprise at least about 70% of a water insoluble compound (based on the weight of the controlled release layer). Preferably, the controlled release layer comprises at least about 80%, more preferably at least about 90% of the water insoluble compound (based on the weight of the controlled release layer). Suitable water-insoluble compounds are, for example, cellulose-derived polymers. These controlled release layer compounds are mixed with a solvent prior to application to the drug-coated pill. Suitable solvents for mixing the controlled release layer compounds are selected from the group consisting of ethanol, isopropanol, acetone and purified water. A mixture of ethanol, acetone and water is preferred for mixing the controlled release layer compound, especially less when the controlled release layer compound is a mixture of ethyl cellulose, dibutyl sebacate and polyethylene glycol.

The process for preparing the extended release component of the beta blocker may include subcoating the initial core/ball to form an inert core. Subcoating the initial core/ball comprises mixing the film coating polymer with one or more plasticizers in a solvent to form a coating mixture. Such mixtures may be solutions, suspensions or slurries for applying a coating layer to a surface. The coating mixture is applied to the initial core/sphere to form a subcoated initial core/sphere that is used as an inert core. The film coating polymer may be a hydrophobic polymer or a hydrophilic polymer, or a combination of both. Suitable film coating polymers may be cellulose derived polymers or polymethylmethacrylate polymers, preferably ethylcellulose. The amount of ethylcellulose is preferably from about 75% to about 85%, more preferably about 80%, based on the total amount by weight of the subcoating. Furthermore, a hydrophobic polymer or a hydrophilic plasticizer, or a combination of several plasticizers, may be used to plasticize the film coating polymer. These compounds, with a polymer coating of the subcoating, are mixed with a solvent prior to application to the initial core/sphere. Suitable solvents for mixing the polymer-coated subcoating compound are selected from the group consisting of ethanol, isopropanol, acetone and purified water. Mixtures of ethanol, acetone and water are preferred for mixing the polymer coated subcoating compound.

Suitable plasticizers for priming the initial core/ball are selected from the group consisting of polyethylene glycol, dibutyl sebacate, and dibutyl phthalate. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as hydrophilic plasticizer and hydrophobic plasticizer, respectively. Preferred amounts of plasticizer for this method are about 10% to about 20% polyethylene glycol and 3% to about 7% dibutyl sebacate, based on the weight of the subcoating. More preferably, about 15% polyethylene glycol and 5% dibutyl sebacate are used as plasticizers.

For extended release coatings, the amount of ethylcellulose is preferably from about 75% to about 85%, more preferably about 80%, based on the total amount by weight of the coating. Suitable plasticizers for the extended release coating are selected from the group consisting of polyethylene glycol, dibutyl sebacate, and dibutyl phthalate. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as hydrophilic plasticizer and hydrophobic plasticizer, respectively. Preferred amounts of plasticizer for use in the method are about 5% to about 20% polyethylene glycol and dibutyl sebacate based on the weight of the extended release coating. More preferably, about 10% polyethylene glycol and 10% dibutyl sebacate act as plasticizers.

In one embodiment, the metoprolol extended release tablet comprises:

in a preferred method of preparing the delayed release portion of the beta-blocker of the composition, the method comprises the steps of; a) providing a sugar pellet as an initial core; b) coating the dragees with a subcoating comprising mixing a thin film of a hydrophobic polymer, a soluble (hydrophilic) plasticizer, and an insoluble (hydrophobic) plasticizer with a solvent mixture of, for example, acetone, 95% ethanol, and water, and spraying the mixture onto the dragees to produce a subcoating on the dragees, thereby yielding an inert core; c) coating subcoating dragees (inert cores) with a drug layer comprising mixing a drug such as metoprolol succinate, and a binder, preferably povidone (PVP K-30), with preferably water to form an aqueous dispersion and applying the dispersion to the subcoating coated dragees (inert cores) to form drug coated dragees; d) applying a third layer to the drug-coated pill comprising dissolving the hydrophobic film coating polymer, the hydrophilic plasticizer, and the hydrophobic plasticizer in a solvent mixture such as acetone, 95% ethanol, and water to form a mixture and spraying the mixture onto the drug-coated pill to produce a controlled release drug-coated pill; e) mixing the controlled release drug coated pellets with a powder mixture of one or more excipients to form a final blend; f) compressing the final blend into tablets, or filling the final blend into capsules; and g) optionally, film coating the tablets for cosmetic purposes.

In this process, the hydrophobic polymer is preferably Ethyl Cellulose (EC), the soluble/hydrophilic plasticizer is preferably polyethylene glycol (PEG), and the insoluble/hydrophobic plasticizer is preferably dibutyl sebacate (DBS). Further, in preparing a mixture for coating sugar pellets with a subcoating, and pellets coated with a controlled release layer coating drug, it is preferable to first dissolve ethyl cellulose in acetone and 95% ethanol, then add PEG and DBS, then add water, and mix the solution until it is homogenized. Preferably, a fluid bed coating machine with insertion needles of the wolstone type is used in the process for spraying the solution or dispersion onto the dragees or drug-coated pellets. In addition, the binder used to coat the subcoated dragees with the drug layer facilitates binding of the drug to the inert core of the subcoated dragees. Further, the ratio of powder mixture to controlled release drug coated pellets in the final tableting blend is preferably from about 20% to about 60% (by weight), more preferably from about 30% to about 50% (by weight), and most preferably from about 35% to about 45% (by weight) in the process. Thus producing a homogeneous final tableting blend and tablet.

Third extended release coating

The extended release phase may comprise at least one high viscosity Hypromellose (HPMC) component. HPMC is a water-soluble matrix-forming polymer used to provide the extended release effect of metoprolol. The viscosity of the HPMC used in the extended release phase may be up to 100.000 cps, for example about 3500 cps and 6000 cps.

A sustained release layer containing a therapeutically effective amount of a beta-blocker such as metoprolol or carvedilol can be prepared with high viscosity hypromellose alone.

In other embodiments, the extended release layer comprises a therapeutically effective amount of a beta-blocker such as metoprolol or carvedilol, at least one high viscosity hypromellose, at least one binder, a low viscosity hypromellose, at least one modified starch, and optionally one or more other pharmaceutically acceptable intragranular components (which include, but are not limited to, a second pharmaceutically active ingredient, other pharmaceutically acceptable excipients and/or adjuvants). In one embodiment, the ratio of high viscosity hypromellose to low viscosity hypromellose is from about 3.3 to about 0.85. In another embodiment, the ratio of high viscosity hypromellose to low viscosity hypromellose is about 3: 1.

Suitably, the low viscosity hypromellose has a viscosity of about 10-30 centipoise. In another embodiment, the low viscosity is about 15 centipoise.

The amount of the at least one binder in the delayed release phase of the bilayer tablet may be from about 0.5% to about 3% w/w. In one embodiment, at least two binders are present in the release layer. Suitably, the amount of the at least one modified starch in the delayed release phase of the bilayer tablet is from about 0.5% to about 3% w/w. In one embodiment, the amount of modified starch is about 1% w/w based on the extended release layer. In one embodiment, at least two modified starches are present in the extended release layer. Suitably, the modified starch is pregelatinized.

Suitably, the high viscosity hypromellose is present in the delayed release phase in an amount of from about 3% to about 7%, based on the weight of the delayed release phase formulation. In another embodiment, the amount of high viscosity hypromellose is from about 4% to about 6%. In yet other embodiments, hypromellose is used in an amount of > 20% in the delayed release phase.

In still other embodiments, the high viscosity HPMC is present in an amount of about 5% w/w based on the weight of the extended release phase formulation.

Suitably, the low viscosity hypromellose is present in the extended release phase in an amount of from about 0.5% to about 3% based on the weight of the extended release phase formulation. In another embodiment, the amount of low viscosity hypromellose is from about 1% to about 2% based on the weight of the extended release phase formulation.

Alternatively, the cellulose derivative of HPMC is present in the extended release granule in a total amount of about 3% to about 10% by weight, based on the total amount of extended release components. This includes both high and low viscosity HPMC.

In one embodiment, the extended release phase comprises metoprolol, povidone, pregelatinized corn starch, and high and low viscosity HPMC.

In one embodiment, the extended release phase comprises carvedilol, povidone, pregelatinized corn starch, and high and low viscosity HPMC.

Tablet and capsule

The film coated beads or spheres may be provided in a sachet or may be formulated as a capsule, for example a hard gelatin capsule, or compressed to form a tablet using known methods of optionally adding other pharmaceutical additives and adding the immediate release and tesofensine components of the beta-blockers described herein. The coated beads to be compressed into tablets are obtained by conventional techniques known to those skilled in the art.

Likewise, suitable further reagents may be added during the process. For example, suitable fillers such as microcrystalline cellulose, lactose monohydrate, talc, sodium stearyl fumarate and the like can be used to provide acceptable compression characteristics to the formulation, such as tablet hardness, during the tableting step.

These additives may be granulated in one of the conventional granulation methods. However, it is preferred to provide a group of additives, such as a powder blend that can be directly compressed into tablets. Such powder mixtures are useful as filler, buffer, disintegrant, glidant, and lubricant mixtures. Furthermore, the ratio of controlled release drug coated pellets to additives in the final (e.g. tableted) blend of the pharmaceutical composition of the invention is particularly important for the preparation of homogeneous products such as tablets.

To produce a homogeneous product, preferably at least 50% (by weight) of the powder mixture may have a particle size of from about 30 μm to about 800 μm, preferably from about 80 μm to about 600 μm, more preferably from about 100 μm to about 300 μm. More preferably, at least 65% (by weight) of the powder mixture has a particle size of from about 30 μm to about 800 μm, preferably from about 80 μm to about 600 μm, more preferably from about 100 μm to about 300 μm. Most preferably, at least 80% (by weight) of the powder mixture has a particle size of from about 30 μm to about 800 μm, preferably from about 80 μm to about 600 μm, most preferably from about 100 μm to about 300 μm.

In addition, the controlled release drug coated pellets are preferably present in the final tableting blend in an amount of about 20% to about 60% (by weight) to facilitate preparation of such a homogeneous product. More preferably, the controlled release drug coated pellets are present in the final tableting blend in an amount of about 30% to about 50% (by weight), most preferably about 35% to about 45% (by weight).

Suitable powder mixtures include, but are not limited to, mixtures of two or more of the following components; starlac (r) (spray-dried compound consisting of 85% alpha-lactose monohydrate and 15% corn starch dry matter from Meggle), cellactose (r) (spray-dried compound consisting of 75% alpha-lactose monohydrate and 25% cellulose powder dry matter from Meggle), parteck (r) (direct compressible sorbitol from Merck KgaA), crospovidone, silicon dioxide, magnesium stearate, talc, zinc stearate, polyoxyethylene stearate, stearic acid, sodium stearyl fumarate cellulose derivatives, microcrystalline cellulose and lactose monohydrate.

If the dosage form is a bilayer tablet or a trilayer tablet, the immediate release layer may be compressed directly onto the previously partially compressed extended release layer or the extended release layer may be compressed onto the previously partially compressed immediate release layer.

The compositions may be formulated by conventional mixing methods, such as granulation, blending, filling and compression. For example, tablets may be prepared by wet granulation, wherein the immediate release phase and the extended release phase are prepared separately. Suitably, for the immediate release phase or the extended release phase, the active drug substance and excipients are sieved and mixed in a high shear mixer granulator or a fluid bed dryer. The blend was granulated as follows: the granulation solution (typically purified water, a disintegrant dissolved/dispersed in purified water, or a drug dissolved/dispersed in purified water or a suitable solvent) is spray added to a high shear mixing granulator or fluid bed dryer. If desired, wetting agents such as surfactants may be added. The resulting granulate (optionally granulated) is dried to a residual moisture content of 1-5% usually by tray drying techniques, fluidized bed drying techniques or microwave drying techniques. The dried granules are milled to produce a uniform particle size, and if necessary blended with extra-granular excipients, typically lubricants and glidants (e.g., magnesium stearate, silicon dioxide). The separately prepared immediate release and extended release granules can then be compressed together using a rotary tablet press (e.g., a bi-layer tablet press), if desired. If the dosage form is a single layer tablet, the extended release granules are mixed with the immediate release extragranular component and compressed together using a rotary tablet press or the like. These resulting tablets can be coated in their entirety in a pan coater with a 1-5% aqueous film coating and then waxed.

Alternatively, tablets may be prepared by direct compression methods. Suitably, the active drug substance and excipients of the immediate release phase and the delayed release phase are separately sieved and mixed in a suitable blender, such as a cone blender, cube blender or V blender. Other excipients are added as necessary and further blended. Separately prepared immediate release and extended release phases may be combined and compressed together using a rotary tablet press as described above. The resulting tablets may be coated in a pan coater.

Tablets may also be prepared using both wet granulation and direct compression methods together. For example, the extended release phase may be prepared by wet granulation as described herein, while the immediate release phase may be prepared by blending excipients for direct compression. The two phases may then be combined and pressed together as described above.

Quick release phase

The immediate release phase may be prepared as follows: commercially available grades of directly compressible beta-blockers, such as metoprolol, and tesofensine, are combined with a lubricant, and, if necessary or desired, one or more disintegrants. Also, if necessary or desired, binders and other excipients and/or adjuvants may be included in the immediate release layer. The beta-blocker and tesofensine in the immediate release layer may be combined with the following components: modified starches such as pregelatinized starch, e.g., corn starch, polyethylene glycol, and disintegrants, or super disintegrants such as croscarmellose sodium or

Binders such as methylcellulose or hypromellose polymers, plasticizers, pigments and lubricants.

The immediate release phase may comprise two different layers of beta-blocker and tesofensine, respectively. Alternatively, immediate release combinations may be incorporated into the same layer. The immediate release phase may also be formulated into the extragranular phase of the tablet, or the immediate release phase may be granulated into one or two different immediate release granules. For tesofensine, the preferred formulation is granulation of tesofensine, compared to direct compression of tesofensine, because of the relatively low dose.

Monolithic dosage form

In one embodiment, there is only a single layer tablet having one delayed release intragranular phase and two immediate release extragranular phases. The extended release phase will consist of the intragranular components of the beta-blocker and excipients described above. These components form extended release particles. The extended release blend may be formed into a pill and then compressed with the extragranular immediate release blend.

Suitable extra-granular components or phases, i.e. the immediate release phase, may be prepared as follows: commercially available grades of beta-blockers, such as metoprolol, and tesofensine citrate, which are directly compressible, are combined with a lubricant, and if necessary or desired one or more disintegrants. As described above for tesofensine, the preferred method is to prepare granules of tesofensine prior to compression. Binders and other excipients and/or adjuvants may be included in the particulate outer phase, if necessary or desired. Alternatively, the extra-granular component may be prepared by combining a beta-blocker, such as metoprolol, and tesofensine, with a modified starch, such as a pregelatinized starch, e.g., corn starch, a disintegrant or super disintegrant, e.g., sodium carboxymethylethylcellulose, a binder, and a lubricant.

Excipient

The compositions of the present invention may include components that function as one or more binders. Suitably, the adhesive may comprise a first adhesive and a second adhesive. Binders suitable for use herein include binders conventionally used in the art, such as gelatin, starch, povidone, polymers and cellulose derivatives or combinations thereof.

Suitably, the Starch is derived from a plant, such as corn (or maize) Starch, modified corn Starch, wheat Starch, modified wheat Starch, potato Starch, or pregelatinized Starch, such as available as Starch 1500G or Prejel; or a combination of two or more thereof.

If the binder comprises a cellulose derivative such as hydroxypropyl cellulose (HPC) (having a low to medium viscosity), for example, it may be commercially available under the trade name

Commercially available from Aqualon division of Hercules Inc., Dow Chemical Company, e.g., Klucel GF, Klucel JF, Klucel LF, and Klucel EF; microcrystalline cellulose (MCC), carboxymethyl cellulose (MC), sodium carboxymethyl ethyl cellulose; or a group of two or more thereofAnd (6) mixing. Combinations of cellulose derivatives with the other binders described above may also be used. Typically, the cellulose derivative is present in the particle in a total amount of about 3% to about 10% by weight, based on the extended release component. It is recognized in the art that certain cellulose derivatives, such as hypromellose, will perform different functions in the formulation depending on the amount used. For example, hypromellose (low or medium viscosity) may be used as a binder, coating agent, or as a matrix forming agent.

When the binder is present as an intragranular component, it is believed that the most appropriate amount of binder may also be present extragranular, for example, up to about another 3.0 wt% > -10.0 wt% intragranular binder content, based on the composition.

In one embodiment, suitably, the starch is a pregelatinized starch. Pregelatinized starch is starch that has been chemically and/or mechanically processed. Typically, pregelatinized starch comprises 5% free amylase, 15% free amylopectin, and 80% unmodified starch. The pregelatinized starch may be derived from corn (or maize), potato or rice starch.

Granulation provides an intimate mixture of the combination of ingredients, which may then be mixed with one or more of the pharmaceutically acceptable extra-granular components of the composition, i.e., with any of the pharmaceutically acceptable ingredients, e.g., diluents, flavoring agents, sweeteners, binders, disintegrants, glidants, lubricants, anti-adherents, anti-static agents, antioxidants, desiccants, or second pharmaceutically active agents. It is contemplated that these same components may be present as both intragranular and extragranular components.

As noted above, other inactive ingredients are present to facilitate compaction, which may optionally be used in relatively small amounts, including lubricants, leveling agents, and binders.

Suitable disintegrants include non-super disintegrants, super disintegrants or a combination of both. Suitable non-superdisintegrants include conventional disintegrants such as starch (corn or maize), pregelatinized starches such as starch 1500G, clays (e.g., VEEGUM (Vanderbilt Minerals, LLC) or bentonite (aluminosilicate clay sorbents consisting essentially of montmorillonite)), microcrystalline cellulose, cellulose or powdered cellulose. It is recognized in the art that some excipients may perform more than one action in a given pharmaceutical formulation. For example, certain excipients such as starch (including pregelatinized starch), and microcrystalline cellulose (identified above as binders) act as both a binder and a disintegrant.

"super-disintegrants" represent a class of disintegrants which can generally be used in lower amounts in pharmaceutical formulations, compared to conventional disintegrants. Examples of super disintegrants include sodium starch glycolate, sodium salts of carboxymethyl starch, modified celluloses, and cross-linked polyvinylpyrrolidone. Sodium starch glycolate by commercial name

(Edward Mendell Co.JRS Pharma)、

(Generichem Corp; DFE Pharma) and

(Blanver, Brazil) is commercially available. Examples of modified cellulose include sodium carboxymethylethylcellulose, sodium salt of carboxymethyl cellulose. Sodium carboxymethyl ethyl cellulose by commercial name

(FMC Corp.)、Nymcel

(Nyma，Netherlands)、

(Avebe，Netherlands)、

(Blanver, Brazil) is commercially available. Examples of crosslinked polyvinylpyrrolidone include crospovidone, and are under the trade name Kollidon

Or Kollidon CL-M (Basf Corp.), and Polyplasdone

(ISP Corp; Ashland) is commercially available. Suitable super disintegrants include sodium carboxymethyl ethyl cellulose or sodium starch glycolate (e.g. sodium starch glycolate)

(JRS Pharma)) or a combination thereof. The super disintegrant may be used extragranular, in an amount of about 0.5% to about 5.0% by weight in the composition. Suitable preservatives or bactericides include potassium sorbate or parabens, i.e., one or more of the hydroxybenzoates, for example, methyl, ethyl, propyl or butyl esters, as appropriate for use alone or as a composition. Esters of p-hydroxybenzoic acid

The trade name is a name that is commercially available, for example,

sodium (Aako BV).

Suitable lubricants include magnesium, calcium or sodium stearate, stearic acid or talc, which may be added in suitable amounts. In one embodiment, the lubricant is magnesium stearate.

Suitable leveling agents include silica (e.g., silica)

(Cabot Corporation)，Syloid^TM(W.R.Grace&Co.)) and colloidal silica (

(Evonik Resource Efficiency GmbH)) may be added in an amount of about 0.5% to about 1% by weight.

The compressed tablets may further comprise a film coating, for example, hypromellose or polyvinyl alcohol-partially hydrolyzed (PVA). Suitably, the film isThe coating is a transparent film coating such as a dye, but opaque film coatings may also be used, such as those obtained when using a film coating in combination with an opacifier or pigment such as titanium dioxide or lakes. For example, one commercially available film coating is available from Colorcon

A coating system.

Medical application

The compositions described herein are useful as pharmaceutical agents, for example, agents for treating, preventing, or ameliorating obesity and/or obesity-related diseases.

Due to the specific combination of the extended and immediate release forms of the combination of a beta-blocker with tesofensine described herein, the compositions of the present application are effective in reducing the cardiovascular side effects of tesofensine while maintaining the therapeutic efficacy of tesofensine.

In one embodiment, the composition of the present application is used as a medicament.

In one embodiment, the composition of the present application is used to treat obesity.

Obesity is defined herein as a medical condition in which excess body fat accumulates to such an extent that it may have an adverse effect on health, often resulting in a reduced life expectancy and/or increased health problems. Thus, in one embodiment, the subject to be treated with the composition of the present application is obese.

Body Mass Index (BMI) is a measure of comparing weight and height. A person is generally considered overweight or pre-obese if the BMI is 25 to 30, and obese if the BMI exceeds 30. The BMI of morbidly obese subjects exceeded 35.

In one embodiment, the subject's BMI is greater than 25kg/m²E.g. higher than 30kg/m²E.g. higher than 35kg/m²E.g. higher than 40kg/m²。

In one embodiment, the subject's BMI is greater than 30kg/m²。

In one embodiment, the subject has a high BMIAt 35kg/m²。

In one embodiment, the compositions of the present application are used to treat obesity-related diseases, such as a disease or disorder selected from: diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, drug obesity, binge eating disorder, bulimia nervosa, binge eating disorder, compulsive binge eating, impaired appetite regulation, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

In one embodiment, the compositions of the present application are used to treat diabetes, such as type 1 diabetes, type 2 diabetes, prediabetes and gestational diabetes. Preferably, the diabetic subject is obese.

In one embodiment, the compositions of the present application are used to treat type 1 diabetes.

In one embodiment, the compositions of the present application are used to treat type 2 diabetes.

In one embodiment, the compositions of the present application are used to treat pre-diabetes.

In one embodiment, the compositions described herein are capable of causing a reduction or amelioration of diabetic complications.

Type 1 diabetes (type 1 diabetes) is a form of diabetes that results from autoimmune destruction of insulin-producing beta cells in the pancreas. In type 1 diabetes, hypertension may reflect the onset of diabetic nephropathy.

Type 2 diabetes is a metabolic disorder characterized by hyperglycemia in the presence of insulin resistance and relative insulin deficiency. Type 2 diabetes accounts for about 90% of the diabetic pathology, with the remaining 10% being primarily due to type 1 diabetes and gestational diabetes. Among people who are genetically predisposed to this disease, obesity is considered to be a major cause of type 2 diabetes.

Prediabetes may be used in place of intermediate hyperglycaemia. Intermediate hyperglycemia is a biochemical state in which a person's blood glucose level is above the normal range, but the diagnostic criteria for diabetes are not yet met. The primary goal of managing intermediate hyperglycemia is to prevent the development of diabetes.

Precursor sugarSubjects with urine disorders may have Impaired Fasting Glucose (IFG) and/or Impaired Glucose Tolerance (IGT) and/or elevated glycated hemoglobin (HbA)_1c) One or more of the levels.

Weight loss can prevent the progression of pre-diabetes to diabetes and can also significantly ameliorate the clinical symptoms of type 2 diabetes. Thus, weight loss is an attractive therapeutic strategy for pre-diabetic subjects and subjects with type 2 diabetes.

In one embodiment, the subject is an obese pre-diabetic patient. In one embodiment, the subject is an obese subject with type 2 diabetes.

Gestational diabetes is a condition in which a woman who has not previously been diagnosed with diabetes exhibits high blood glucose levels during pregnancy (particularly during the third trimester of pregnancy). Gestational diabetes results when insulin receptor function is abnormal.

WHO diabetes diagnostic criteria are shown in the table below.

Venous blood glucose 2 hours after intake of 75g oral glucose load

A subject benefiting from treatment with a composition of the present application may also be a subject suffering from an obesity related disease or condition, for example selected from one of the following diseases or conditions: diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, drug obesity, binge eating disorder, bulimia nervosa, binge eating disorder, compulsive binge eating, impaired appetite regulation, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

In one embodiment, the compositions of the present application are used to treat metabolic syndrome, for example, to treat an obese subject suffering from metabolic syndrome.

In one embodiment, the compositions of the present application are used to treat fatty liver disease, such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). The subject suffering from NAFLD or NASH is preferably obese.

In one embodiment, the compositions of the present application are used to treat non-alcoholic fatty liver disease (NAFLD).

In one embodiment, the composition of the present application is used for the treatment of nonalcoholic steatohepatitis (NASH).

Nonalcoholic fatty liver disease (NAFLD) is a cause of fatty liver, which is produced when fat is deposited in the liver (steatosis) due to causes other than excessive drinking. NAFLD is the most common liver disease in western industrialized countries. NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia, diabetes (type II) and hypertension). Nonalcoholic steatohepatitis (NASH) is the most extreme form of NAFLD and is the leading cause of cirrhosis. NASH is a condition in which steatosis is combined with inflammation and fibrosis (steatohepatitis).

In one embodiment, the compositions of the present application are used in a method of reducing liver fat and/or visceral adiposity. Reduction of liver fat and/or visceral obesity has been shown to be effective in the treatment of fatty liver disease. Tesofensine can significantly reduce waist circumference and sagittal diameter (Astrup et al, 2008, Lancet 372: 1906-13); thus tesofensine can reduce visceral adiposity.

The compositions of the present application are preferably administered once daily to a subject in need thereof. However, in certain embodiments, the compositions may be administered once daily, e.g., twice daily, or less than once daily, e.g., once every two days or once every three days, depending on the particular formulation and concentrations of the individual components of the composition. The subject of treatment is preferably a human, for example an adult of 18 years or older.

In one embodiment, the present application relates to the use of a composition disclosed herein for the preparation of a medicament for the treatment of diabetes, obesity, or obesity-related diseases.

The following non-limiting examples illustrate advantageous properties of the compositions.

Examples

Example 1:

controlled release metoprolol succinate pellets prepared as described in WO 2007/097770 were removed with an efficacy of 51.19% metoprolol succinate (corresponding to 53.88% metoprolol tartrate) and mixed with microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl cellulose and magnesium stearate. The mixture was compressed on a rotary tablet press into tablets, each tablet having a tablet weight of 400mg and a size of 7x14mm, each tablet containing 100mg of metoprolol tartrate equivalent. The tablet will release the drug at a zero order release rate.

Metoprolol succinate pill	371.2
		Microcrystalline cellulose	240.0
Lactose monohydrate	164.8
		Sodium carboxymethyl ethyl cellulose	16.0
Magnesium stearate	8.0
		Total of	800.0

Metoprolol 100mg extended release tablets (containing 95mg metoprolol succinate) are films coated with an aqueous film containing tesofensine citrate in a perforated drum coater. The following table gives the film compositions. 125mg of the film solution was administered for each tablet, which corresponds to an increase of about 2.2% in tablet weight. The spraying conditions were controlled to outlet air temperature 40-45 ℃.

The subcoated metoprolol tablets were further coated with the final coating solution given in the table below. 250mg of the film solution was administered for each tablet, which corresponds to an increase in tablet weight of about 16.0%. The spraying conditions were controlled to outlet air temperature 43-48 ℃. The final product contained 100mg of extended release metoprolol and 25mg of immediate release metoprolol.

Example 2:

the procedure is as in example 1, except that a film-action subcoat of metoprolol is used and a tesofensine coating is used as the final coating.

Example 3:

the procedure is as in example 1 except that controlled release pellets of metoprolol are used as described in US 7,959,947, example 3, of AstraZeneca.

Example 4:

metoprolol pills are prepared as follows: metoprolol succinate is mixed with microcrystalline cellulose and water is added in a high shear mixer until proper wetting is achieved. The wet mass was extruded through a Bepex extruder and the dosage form strands (form strands) were squared on a pelletizer. The resulting pellets, about 1mm in diameter, were dried in a fluidized bed at an inlet air temperature of 60 ℃. Metoprolol pellets were film coated with a film in a fluidized bed with bottom spray to control the release profile. An increase of about 5% in weight is expected.

Ethyl cellulose 7cps	6.75g
		Methyl cellulose E15	0.75g
96 percent of ethanol	69.375g
		Water (W)	23.125
Total of	100.0

Chips were prepared from the batch composition of example 1, wherein the weight of the chips was 400 mg. The subcoating and final coating were applied as described in example 1. The final product was a tablet containing 100mg of extended release metoprolol and 25mg of immediate release metoprolol.

Example 5:

tesofensine citrate and microcrystalline cellulose were mixed for 20 minutes. Metoprolol succinate, the rest of the microcrystalline cellulose and colloidal silicon dioxide were mixed for an additional 20 minutes. Controlled release metoprolol pellets as described in example 1 were added to the blend and mixed for 20 minutes. The blend was filled into hard gelatin capsules size 1.

Metoprolol succinate	23.75g
		Tesofensine citrate	0.50g
		Microcrystalline cellulose	88.65g
Silica, colloids	1.50g
		Controlled release metoprolol pill 53.88%	185.60g
Total of	300g

The final product was a gelatin capsule containing 100mg of extended release metoprolol and 25mg of immediate release metoprolol.

Example 6:

metoprolol extended release tablet having a single tesofensine film coating and an immediate release metoprolol film coating

Metoprolol 100mg extended release tablets from example 1 (containing 95mg metoprolol succinate) were film coated with an aqueous film containing tesofensine citrate in a perforated drum coater. The following table gives the film compositions. 370.4mg of the film solution was administered for each tablet, which corresponds to an increase in tablet weight of about 4.2%. The spraying conditions were controlled to outlet air temperature of 45-50 ℃.

Methyl cellulose E15	8.0
		Polyethylene glycol 6000	0.8
Tesofensine citrate	0.27
		Water (W)	190.93
Total of	200.0

The subcoated metoprolol tablets were further coated with the final coating solution given in the table below. 312.5mg of the film solution was administered for each tablet, which corresponds to an approximately 15.7% increase in tablet weight. The spraying conditions were controlled to outlet air temperatures of 46-49 ℃.

Release of metoprolol was tested according to the united states pharmacopeia monograph, test 1 (united states official pharmacopeia committee, day 1/8 2012) of metoprolol succinate extended release tablets. The results were:

time (h)	Amount of elution (%)
		1	23
4	29
		8	47
20	102

Tesofensine release was tested at 1 hour time point and was found to be complete.

The release profile of metoprolol from 100mg extended release tablets and 25mg immediate release tablets of metoprolol with tesofensine film-and immediate release films administered alone is shown in figure 3.

Example 7:

metoprolol extended release tablet having a film coating containing both tesofensine and immediate release metoprolol.

Metoprolol 100mg extended release tablets from example 1 (containing 95mg metoprolol succinate) were film coated with an aqueous film containing tesofensine citrate and metoprolol succinate in a perforated drum coater. The following table gives the film compositions. 312.5mg of the film solution was administered for each tablet, which corresponds to an approximately 16.5% increase in tablet weight. The spraying conditions were controlled to outlet air temperature of 45-50 ℃.

Release of metoprolol was tested according to the united states pharmacopeia monograph, test 1 (united states official pharmacopeia committee, day 1/8 2012) of metoprolol succinate extended release tablets. The results were:

time (h)	Amount of elution (%)
		1	24
4	35
		8	55
20	105

Tesofensine release was tested at 1 hour time point and was found to be complete.

The release profile of metoprolol from 100mg extended release tablets and 25mg immediate release tablets of metoprolol with tesofensine/metoprolol film administered in combination is shown in figure 3.

Example 8:

carvedilol 80mg extended release tablets with separate tesofensine coating and carvedilol immediate release coating.

The tablets contained 0.5mg of immediate release tesofensine, 80mg of delayed release carvedilol and 20mg of immediate release carvedilol, i.e. an ER: IR ratio of 80: 20.

Carvedilol 400mg/g pills are prepared as follows: carvedilol is mixed with microcrystalline cellulose and water is added in a high shear mixer until proper wetting is achieved. The wet mass was extruded through a Bepex extruder and the dosage form strands were squared on a pelletizer. The resulting pellets, about 1mm in diameter, were dried in a fluidized bed at an inlet air temperature of 60 ℃. Carvedilol pellets are film coated with a film in a fluidized bed with a bottom spray to control the release profile. An increase of about 5% in weight is expected.

Carvedilol	252g
		Microcrystalline cellulose	348g
Water (W)	200g
		Total of	800.0

Ethyl cellulose 7cps	6.75g
		Methyl cellulose E15	0.75g
96 percent of ethanol	69.375g
		Water (W)	23.125
Total of	100.0

Carvedilol 80mg extended release tablets are prepared as follows: carvedilol 400mg/g pellets were mixed with microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl ethyl cellulose and magnesium stearate. The mixture was compressed on a rotary tablet press into tablets each having a tablet weight of 400mg and a size of 7x14mm, each tablet containing 80mg of carvedilol. The tablet will release the drug at a zero order release rate.

Carvedilol 80mg of the extended release tablet was film coated with an aqueous film containing tesofensine citrate in a perforated drum coater. The following table gives the film compositions. 370.4mg of the film solution was administered for each tablet, which corresponds to an increase in tablet weight of about 4.2%. The spraying conditions were controlled to outlet air temperature of 45-50 ℃.

Methyl cellulose E15	8.0
		Polyethylene glycol 6000	0.8
Tesofensine citrate	0.27
		Water (W)	190.93
Total of	200.0

The subcoated carvedilol/tesofensine tablets were further coated with the final coating dispersion given in the table below. 313.6mg of film solution was administered for each tablet, which corresponds to an approximately 14.8% increase in tablet weight. The spraying conditions were controlled to outlet air temperatures of 46-49 ℃. The amount of carvedilol in the immediate release film coating corresponds to 20mg of carvedilol.

Figure 4 depicts the expected dissolution profile of carvedilol in a pharmaceutical product containing 80mg of delayed release carvedilol and 20mg of immediate release carvedilol. Dissolution profiles were measured using a USP type 1 dissolution instrument using 500ml pH 1.45 for 2 hours, then increasing the pH to 7 and increasing the volume to 900 ml. The test was carried out at 37 ℃ with stirring at 50rpm for 20 hours.

Example 9:

carvedilol 40mg extended release tablets with separate tesofensine coating and carvedilol immediate release coating.

The tablets contained 0.5mg of immediate release tesofensine, 40mg of delayed release carvedilol and 10mg of immediate release carvedilol, i.e. an ER: IR ratio of 80: 20.

Carvedilol 40mg extended release tablets were prepared as follows: carvedilol 400mg/g pellets (from example 8) were mixed with microcrystalline cellulose, lactose monohydrate, sodium carboxymethyl ethyl cellulose and magnesium stearate. The mixture was compressed on a rotary tablet press into tablets each having a tablet weight of 400mg and a size of 7x14mm, each tablet containing 40mg of carvedilol. The tablet will release the drug at a zero order release rate.

Carvedilol 400mg/g pill	200.0
		Microcrystalline cellulose	320.0
Lactose monohydrate	255.8
		Sodium carboxymethyl ethyl cellulose	16.0
Magnesium stearate	8.0
		Total of	800.0

Carvedilol 40mg of the extended release tablet was film coated with an aqueous film containing tesofensine citrate in a perforated drum coater. The following table gives the film compositions. 370.4mg of the film solution was administered for each tablet, which corresponds to an increase in tablet weight of about 4.2%. The spraying conditions were controlled to outlet air temperature of 45-50 ℃.

Methyl cellulose E15	8.0
		Polyethylene glycol 6000	0.8
Tesofensine citrate	0.27
		Water (W)	190.93
Total of	200.0

The subcoated carvedilol 40mg extended release/tesofensine tablets were further coated with the final coating dispersion given in the table below. 313.6mg of film solution was administered for each tablet, which corresponds to an increase in tablet weight of about 12.4%. The spraying conditions were controlled to outlet air temperatures of 46-49 ℃. The amount of carvedilol in the immediate release film coating corresponds to 10mg of carvedilol.

Figure 4 depicts the expected dissolution profile of carvedilol in a pharmaceutical product containing 40mg of delayed release carvedilol and 10mg of immediate release carvedilol. Dissolution profiles were measured using a USP type 1 dissolution instrument using 500ml pH 1.45 for 2 hours, then increasing the pH to 7 and increasing the volume to 900 ml. The test was carried out at 37 ℃ with stirring at 50rpm for 20 hours.

Claims (38)

1. A pharmaceutical composition comprising a. a first composition comprising an extended release composition of an active pharmaceutical ingredient (API) selected from the group consisting of metoprolol and pharmaceutically acceptable salts thereof, b. a second composition comprising an active pharmaceutical ingredient (API) selected from Tesofensine and pharmaceutically acceptable salts thereof, and c. A third composition comprising an immediate release composition of an active pharmaceutical ingredient (API) selected from the group consisting of metoprolol and pharmaceutically acceptable salts thereof wherein the pharmaceutical composition is in the form of a pharmaceutical dosage form selected from tablets or capsules. 2. The composition of claim 1, wherein the pharmaceutically acceptable salt of metoprolol is selected from the group consisting of metoprolol succinate and metoprolol tartrate. 3. The composition of claim 1, wherein the Tesofensine and pharmaceutically acceptable salts thereof are selected from the group consisting of free base, citrate, and tartrate. 4. The composition of claim 1, wherein the second composition is a first coating applied to the first composition. 5. The composition of claim 4, wherein the third composition is a second coating applied to the first coating. 6. The composition of claim 1, wherein the first composition is coated by a coating comprising the second composition and the third composition. 7. The composition of claim 1, wherein the first composition constitutes a tablet core coated with a coating comprising the second composition and the third composition. 8. The composition of claim 1, wherein the first composition comprises a pill comprising: a. Inert pellet core; b. a drug layer comprising the active pharmaceutical ingredient, the layer covering the inert core; and c. Controlled release layer thereon. 9. The composition of claim 8, wherein the inert pellet core comprises a sugar pellet coated with a plasticized film wrap of a hydrophobic film coating polymer plasticized with a hydrophilic plasticizer and a hydrophobic plasticizer a subcoat; the drug layer comprises an API and a binder; the controlled release layer comprises a plasticized film coat of a hydrophobic film coating polymer plasticized with a hydrophilic plasticizer and a hydrophobic plasticizer, and wherein the The pellets are mixed with a final tableting blend comprising a powder mix of one or more of fillers, disintegrants, glidants and/or lubricants. 10. The composition of claim 9, wherein the hydrophobic film coating polymer comprises ethyl cellulose, the hydrophilic plasticizer comprises polyethylene glycol, and the hydrophobic plasticizer comprises dibutyl sebacate , the API is metoprolol succinate, the binder includes povidone, and the powder mix includes starlac, syloid, crospovidone, and magnesium stearate. 11. The composition of claim 1, wherein the first composition comprises a controlled release layer comprising a mixture of the following components: a. Ethyl acrylate/methyl methacrylate copolymer, b. Surfactant, and c. sodium stearyl fumarate, wherein the controlled release layer has been deposited from an aqueous liquid, and the content of the ethyl acrylate/methyl methacrylate copolymer in the film coating ranges from 80 to 99.5 w/w %. 12. The composition of claim 1, wherein the second composition and the third composition comprise pills comprising: a. Inert pellet core; b. A drug layer comprising the active drug ingredient, the drug layer covering the inert core. 13. The composition of claim 1, wherein the composition is in the form of a tablet. 14. The composition of claim 1, wherein the composition is in the form of a capsule. 15. The composition of claim 13, wherein the tablet comprises an external cosmetic film coating. 16. The composition of claim 1, wherein one dosage form comprises an amount of said first composition comprising 25-200 mg of API. 17. The composition of claim 16, wherein one dosage form comprises an amount of said first composition comprising 50-150 mg of API. 18. The composition of claim 1, wherein one dosage form comprises an amount of the second composition comprising 0.1-1 mg of API. 19. The composition of claim 18, wherein one dosage form comprises an amount of said second composition comprising 0.2-0.8 mg of API. 20. The composition of claim 18, wherein one dosage form comprises an amount of the second composition comprising 0.25 mg of the API. 21. The composition of claim 18, wherein one dosage form comprises an amount of the second composition comprising 0.5 mg of the API. 22. The composition of claim 18, wherein one dosage form comprises an amount of the second composition comprising 0.75 mg of the API. 23. The composition of claim 1, wherein one dosage form comprises an amount of said third composition comprising 5-100 mg of API. 24. The composition of claim 23, wherein one dosage form comprises an amount of said third composition comprising 10-50 mg of API. 25. The composition of claim 23, wherein one dosage form comprises an amount of said third composition comprising 10-20 mg of API. 26. The composition of claim 23, wherein one dosage form comprises an amount of the third composition comprising 10 mg of the API. 27. The composition of claim 1, wherein the ratio of extended release metoprolol to immediate release metoprolol is 75-95:25-5. 28. The composition of claim 27, wherein the ratio of extended release metoprolol to immediate release metoprolol is 75:25. 29. The composition of claim 1, comprising: 25-200 mg extended-release metoprolol, 5-50 mg immediate-release metoprolol, and 0.1-1.5 mg tesofensine. 30. The composition of any one of claims 1-29 for use as a medicament. 31. The composition of any one of claims 1-29 for use in the treatment of obesity or an obesity-related disease. 32. A composition for use in claim 31 for the treatment of diabetes. 33. The composition for use in claim 32, wherein the diabetes is type 2 diabetes. 34. The composition for use in claim 32, wherein the diabetes is prediabetes. 35. A composition for use in claim 31 for the treatment of a disease or condition selected from the group consisting of metabolic syndrome, dyslipidemia, atherosclerosis, drug-induced obesity, binge eating disorder, bulimia nervosa, eczema Eating disorder, compulsive binge eating, impaired appetite regulation, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). 36. The composition for use in claim 31, wherein the metoprolol prevents or reduces the cardiovascular side effects of Tesofensine. 37. The composition for use in claim 31, wherein the composition is administered once daily. 38. Use of a composition according to any one of claims 1 to 29 in the manufacture of a medicament for the treatment of diabetes, obesity or obesity-related diseases.

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